Steroid Sparing Efficacy of Voclosporin in Active Lupus Nephritis: Stable Kidney Function and Blood Pressure without Electrolyte Complications at 48 Weeks.
JA Tumlin, B Rovin, MM Rahman, WF Pendergraft, D Jayne, N Solomons, RB Huizinga Disclosures
JA Tumlin: Research grant, Consultant for Aurinia B Rovin: Research grant MM Rahman: Research grant WF Pendergraft: Research grant D Jayne: Board Member for Aurinia N Solomons: Employee of Aurinia RB Huizinga: Employee of Aurinia SLE & LN Overview & Symptomatology
SLE is a chronic, complex and often CENTRAL NERVOUS SYSTEM disabling autoimmune disorder Headaches, dizziness, memory disturbances, vision problems, Affects over 500K Highly heterogeneous, seizures, stroke, people in the US affecting range of organ or changes in behavior HEART (mostly women)1 & tissue systems1 Chest pains, LUNGS heart murmurs LN is an inflammation of the kidneys caused Pleuritis, inflammation, by SLE & represents serious progression or pneumonia KIDNEYS Up to 60% of SLE patients develop LN2 Inflammation Leakage of blood proteins into the urine (proteinuria) is clinical sign of LN4 BLOOD Straightforward disease outcomes—early Anemia, decreased response correlates w/long term outcomes; white cells, measured by proteinuria2 increased risk of blood clots Debilitating and costly, often leading to ESRD, dialysis, renal transplant, and death2 Severe LN progresses to ESRD within 15 NO FDA OR EMA APPROVED LN THERAPIES years of diagnosis in 10% to 30% of patients3
Lupus Foundation of America website: http://www.lupus.org/about/statistics-on-lupus 1. NIDDK, Lupus Nephritis. https://www.niddk.nih.gov/health-information/health-topics/kidney-disease/lupus-nephritis/Pages/index.aspx. Accessed July 26, 2016. 2. Maroz N, Segal MS. Am J Med Sci. 2013;346(4):319-23. Lupus Foundation of America, http://www.lupus.org/resources/15-questions-kidney-issues-and-lupus1. Accessed July 26, 2016. Renal Remission is Critical in Preventing ESRD
120% Survival without ESRD Based on Response to Treatment
100% 8%
80% 57%
60% 87%
92% 40%
20% 43%
13% 0% Complete Remission Partial Remission No Response Not on Dialysis @ 10 years On Dialysis at 10 years
1. Chen YE, et al. Clin J Am Soc Nephrol. 2008;3(1):46-53. Response = 50% reduction in proteinuria; Remission = proteinuria <.33 g/24 hrs.. Standard Therapy for Proliferative Lupus Nephritis
Proliferative LN: Give IV Methylprednisolone 0.5-1g/d for 1-3 days followed by Oral Prednisone 1mg/kg/d ideal body weight, Maximum 80 mg/d, Taper Over Weeks
24 week Partial & Complete Response PLUS: Rates with Cyclophosphamide and MMF2
60% 56% 53% 50%
40% PO Cyclophosphamide EURO-LUPUS REGIMEN 30% IV Cyclophosphamide 1-1.5mg/kg/d, IV Cyclophosphamide Oral MMF 2 0.5-1g/m Monthly maximum 150 mg/d for 500 mg every 2 weeks for 2-3g/d for 20% for 6 months 2-4 months 3 months: LOW-DOSE- 6 months 9% 10% 8% Results of ALMS Trial showed majority of A better solution is needed to 0% patients failed to achieve CR at 24 weeks for Partial Response Complete Remission improve renal response rates for LN both of these first-line therapeutics2 Cyclophosphamide MMF
1. Hahn BH, et al. Arthritis Care Res (Hoboken). 2012;64(6):797-808. 2. Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112 Structural Differences in Voclosporin-Increased Potency and Potential Reduced Clinical Toxicity
Voclosporin Cyclosporin
Modification results in: Clinical benefits*: • Reduced risk of diabetes (vs. TAC) 1) Predictable PK/PD relationship • Allows for flat dosing • No impact on MPA levels 2) 3-4 fold Increased Potency • Improved lipid profile (vs. CSA) 3) Altered metabolic profile –faster elimination of metabolites
*Existing CNI’s (cyclosporine & Tacrolimus) are not approved for Lupus in the EU/US Voclosporin - Compared to Legacy CNIs 1,2,3
2 100 100 Concentration (PK) 90 80 75 CSA 600 VCS 70 60 TAC
CsA 50 50 %CNI
Increased Potency %CNI 500 40 vs. cyclosporine A, 30 25 20 r = 0.5 r = 0.7 400 allowing lower 10 0 0 dosing 0 10 20 30 40 50 60 0 250 500 750 1,000 1,250 1,500 300 Limited inter & Limited inter & 1 Concentration (ng/mL) Concentration (ng/mL) requirements intra patient intra patient 200 variability – variability – 100 Concentration (ng/mL) Concentration 100 allowing flat 75 allowing flat 1,3 0 1,3 dosing 0 2 4 6 8 dosing 50 VCS Time (h) %CNI Immunosuppression (PD) 2 25 r = 0.8
55 Limited incidence 0 50 VCS Four Fold 20 0 100 200 300 400 500 600 700 800 900 CsA of glucose Concentration (ng/mL) 45 Greater 40 intolerance & 15 CNI Induced Diabetes 35 Potency diabetes at 30
Inhibition (%) Inhibition 10 25 targeted doses vs. 2 20 tacrolimus 15 5
10 Cases diabetes onsetmonths) of new(12 Calcineurin
5 0 Low conc. Mid conc. 0 0 2 4 6 8 Voclosporin Tacrolimus Time (h) 1. Aurinia Data on fil 3. AURA-LV Data on file 2. Busque S, et al. Am J Transplant. 2011;11(12):2675-2684 & AURA LV Data Synergistic Impact of Calcineurin Inhibition in LN
By inhibiting calcineurin, voclosporin blocks IL-2 CNI’s have shown an ability to stabilize podocytes in the kidney, expression and T cell–mediated immune responses1,2 which protects against podocytopathy and proteinuria3-5
Tissue Actin damage cytoskeleton Dephosphorylated Voclosporin synaptopodin breaks up and APC destabilizes the actin cytoskeleton of the podocyte Voclosporin Synaptopodin Cytoplasm T cell receptor
Nucleus
IL-2 INF-gamma Cell-mediated TNF-alpha immune Glomerular basement membrane response
APC, antigen-presenting cell; IL, interleukin; INF, interferon; LN, lupus nephritis; NFAT, nuclear factor of activated T-cells; TNF, tumor necrosis factor. 1. Mak A, Kow NY. J Immunol Res. 2014;2014:419029. doi:10.1155/2014/419029. Zhang B, Shi W. Int J Nephrol. 2012;2012:809456. 2. Wang Y, et al. J Am Soc Nephrol. 2010;21(10):1657-1666. Faul C. et al. Nat Med. 2008;14(9):931-938. AURA Study Design: Phase IIB
Study was designed to evaluate whether voclosporin added to SoC can increase speed of remission & overall remission rates in the presence of extremely low steroids
Primary endpoint 24 weeks Secondary endpoint 48 weeks
VOCLOSPORIN 23.7 mg bid VOCLOSPORIN 23.7 mg bid MMF 2 g + oral corticosteroids
VOCLOSPORIN 39.5 mg bid VOCLOSPORIN 39.5 mg bid
MMF 2 g + oral corticosteroids N=265
PLACEBO PLACEBO 1:1 Randomization 1:1 MMF 2 g + oral corticosteroids AURA Key Inclusion Criteria & Outcome Measures
KEY INCLUSION CRITERIA Indicative of Diagnosis of SLE according Biopsy proven LN [Class III, IV or Class III/IV proteinuria of Class V (alone or in combination ≥1.5 mg/mg highly active to ACR criteria w/Class III or IV)] OR Class V ≥2 mg/mg* disease PRIMARY OUTCOME MEASURES
The proportion of subjects achieving complete remission (CR) at 24 weeks Normal, stable renal function (≥60 CR is defined as: Confirmed urinary mL/min/1.73m2 or no confirmed decrease from protein/creatinine ratio of ≤0.5 mg/mg baseline in eGFR of ≥20%) + Presence of sustained, low dose steroids (≤10mg No administration of rescue medications prednisone from week 16-24)
KEY SECONDARY OUTCOME
Partial Remission, Time to Remission, Time to Partial Remission, Durability of remission and extra-renal activity (SLEDAI) at 24 & 48 weeks *≥2 mg/mg refers to Class V patients Baseline Demographic and Clinical Characteristics Age and Sex were similar across treatment groups Control Voclosporin Voclosporin Total 23.7 mg BID 39.5 mg BID N = 88 N=89 N=88 N = 265 Biopsy Class n (%) Pure Class V 13 (15.0) 12 (13.5) 14 (15.9) 39 (14.7) Non Class V 75 (85.0) 77 (86.5) 74 (84.1) 226 (85.3) Baseline eGFR CKD-EPI Mean ± SD 100 ±26.9 95 ±28.4 105 ±27.5 100 ± 27.8 Median 100 95 109 101 Min/Max 49, 153 41, 148 42, 165 41, 165 Baseline uPCR (mg/mg) Mean ±SD 4.4 ± 3.58 5.2 ± 4.15 4.5 ± 3.03 4.7 ± 3.62 Median 3.1 3.8 3.7 3.5 Min/Max 0.8, 19.3 0.8, 29.7 1.0, 17.4 0.8, 29.7 Renal Response (Complete Remission) at 24 and 48 Weeks
First global trial in active LN to meet its primary endpoint 24 Odds ratio 48 Odds Ratio Endpoint Treatment P-value* P-value* weeks (95% CI) weeks (95% CI)
23.7mg VCS BID 32.6% 2.03 (1.01, 4.05) p=.045 49.4% 3.21 (1.68, 6.13) p<.001
Complete Remission 39.5mg VCS BID 27.3% 1.59 (0.78, 3.27) p=.204 39.8% 2.10 (1.09, 4.02) p=.026 (CR)
Control 19.3% NA NA 23.9% NA NA
23.7mg VCS BID 70% 2.33 (1.68, 6.13) p=.007 68% 2.34 (1.27, 4.33) p=.007
Partial Remission 39.5mg VCS BID 66% 2.03 (1.10, 3.76) p=.024 72% 2.68 (1.43, 5.02) p=.002 (PR)
Control 49% NA NA 48% NA NA
12 Improved CR & PR Over Time with Voclosporin
23.7mg BID VCS demonstrates statistically significant CR & PR rates at 24 & 48 weeks
Progression to Complete Remission Progression to Partial Remission 60% 100%
90% 50% p<.001 80% p=.007 p=.002 70% 40% p=.007 p=.045 p=.026 60% p=.024
30% 50%
40%
20% 30% Patients achieving CR achieving Patients 20% 10% 10%
0% 0% Baseline 24 weeks 48 weeks
Control VCS 23.7mg BID VCS 39.5mg BID Control VCS 23.7mg BID VCS 39.5mg BID 100% of patients in the low-dose arm in complete remission at 24 weeks stay in CR
13 AURA: Pre-specified Analysis: Speed of Remission (renal response)
VCS showed a statistically significant faster speed of remission compared to the control group
P-Value <0.001 for both LD-VCS and HD-VCS
14 UPCR (mg/mg) at 48 and 50 weeks: UPCR remains stable 2 weeks off treatment
Change from Baseline in UPCR (mg/mg)
5.161
4.433 4.476
p=<.009 vs. 1.956 1.763 p=<.001 vs. control control 1.101 1.204 0.689 0.821
PLACEBO VOCLOSPORIN 23.7 MG BID VOCLOSPORIN 39.5 MG BID Baseline Week 48 Week 50
15 Oral Steroid Dosing Is Similar Between Study Arms
Placebo Voclosporin 23.7 Voclosporin mg BID N=89 39.5 mg BID N = 88 N=88 Weight ≥ 45 kg Mean Daily Dose (mg) Duration over 48 Weeks n 79 80 84 Mean (SD) 8.0 (5.14) 7.9 (5.98) 7.9 (6.45) Median 5.4 5.5 5.4 Min, Max 4.0, 26.9 3.7, 44.0 3.9, 40.0 Week 16 Oral Corticosteroid Dose Level ≤2.5mg 58 (71.6) 61 (76.3) 63 (75.0) >2.5mg 15 (18.5) 11 (13.8) 16 (19.0) Withdrawal from Study Prior to Week 16 8 (9.9) 8 (10.0) 5 (6.0)
16 Serum Albumin (Mean) Over Time 48 weeks
4.3
p<0.001 vs. control 4.1
p<0.001 vs. control 3.9
3.7
3.5 Albumin(g/dL) 3.3
3.1
2.9
2.7 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Visit Low Dose High Dose Placebo
17 C3 (Mean) Over Time 48 weeks
145
125
105
) 85
dL C3 (mg/ C3 65
45
25 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Visit
Low Dose High Dose Placebo
18 C4 (Mean Over Time 48 weeks
30
25
20 c4 (mg/dL) c4 15
10
5 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Visit
Low Dose High Dose Placebo
19 Anti-dsDNA (Mean) Over Time 48 weeks
145
125
105
85
dsDNAAntibody (IU/mL) 65
p=.011 vs. control
45 p=.006 vs. control
25 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Visit
LD VCS HD VCS Control
20 eGFR (mL/min/1.73m²) Over Time
eGFR Returns to Baseline After 48 Weeks of Treatment
*eGFR values > 90 mL/min corrected to 90 mL/min. 21 AURA: Potassium (Mean) over 48 weeks
Potassium Stays Within Normal Range
6 Potassium (Mean) Over Time 5.5
5
4.5
4
3.5 Potassium Potassium (mmol/L)
3
2.5
2 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Week 50 Visit Low Dose High Dose Placebo
22 AURA: Magnesium (Mean) over 48 weeks
Magnesium Stays Within Normal Range
3.00
2.75 Magnesium (Mean) Over Time
2.50
2.25
2.00
1.75
1.50
1.25
Magnesium Magnesium (mg/dL) 1.00
0.75
0.50
0.25
0.00 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Week 50 Visit Low Dose High Dose Placebo
23 AURA: Blood Pressure (BP) (Mean) over 48 weeks
No significant difference in blood pressure over the 48-week treatment period
160 Systolic BP (Mean) Over Time
140
120 (mmHg)
100
Systolic Systolic BloodPressure Low Dose High Dose Placebo 80 Baseline Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Visit
110 Diastolic BP (Mean) Over Time 100
90
80
70
60
Low Dose High Dose Placebo Diastolic Diastolic BloodPressure (mmHg) 50 Baseline Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Visit
24 Differential Expression of Calcineurin Catalytic Subunit Isoforms Along Nephron
Note: Calcineurin Ab isoform predominate in Distal Nephron Aa Aa Na+ Cl-
Aa
NaK2CL Ab Ab
CAN Aa CAN Ab
Tumlin et.al. Am. J. Phys. - Renal October 269, F558-F563, 1995
25 Activation of NaCl-Co-Transporter Activity in DCT is Mediated by Calcineurin Aa Isoform
Calcineurin Aa Isoform Predominate in Distal Convoluted Tubule
DCT CAN Aa Na+ Cl-
Tacrolimus in MTAL Na-Cl Co-trans activity
Potential Voclosporin-selective inhibition of CAN Ab isoform could lead to reduced NaCl cotransporter activity
Hoorn et.al. Nature Medicine, Vol 17(10), 1304-1310, 2011 Summary of AEs & Historical Comparison
Treatment Emergent Adverse Events Control VCS 23.7 mg BID VCS 39.5 mg BID (TEAE)* N = 88 N = 89 N = 88 n (%) n (%) n (%) *includes TEAES following treatment period Any TEAE 78 (88.6) 82 (92.1) 85 (96.6) Any Serious TEAE 17 (19.3) 25 (28.1) 22 (25.0) Any TEAE with Outcome of Death 4 (4.5) 10 (11.2) 2 (2.3) Any Treatment-Related TEAE 15 (17.0) 45 (50.6) 55 (62.5) Any Serious Treatment-Related TEAE 1 (1.1) 4 (4.5) 7 (8.0)
AURA-LV4 ALMS Induction2 Abatacept Study1 Ocrelizumab Study3 N=265 N=364 MMF N = 298 N=378 (to Dec 18th/16) SAE’s, Subjects, n (%) 59 (22.3%) (25.3%) 92 (30.9%) 107 (28.3%) Serious Infections, 29 (10.9%) (10.9%) 58 (19.5%) 64 (16.9%) Subjects n (%) Deaths, Subjects, n (%) 13 (4.9%) 14 (3.8%) 14 (4.7%) 14 (3.7%) 27 Key Adverse Events
Control VCS 23.7 mg BID VCS 39.5 mg BID N = 88 N = 89 N = 88 n (%) n (%) n (%)
Diarrhea 14 (15.9) 16 (18.0) 14 (15.9) Nausea 7 (8.0) 16 (18.0) 11 (12.5) Cough 3 (3.4) 16 (18.0) 5 (5.7) Vomiting 10 (11.4) 15 (16.9) 9 (10.2) Anemia 7 (8.0) 13 (14.6) 14 (15.9) Upper respiratory tract infection 14 (15.9) 12 (13.5) 18 (20.5) Urinary tract infection 5 (5.7) 8 (9.0) 6 (6.8) Pneumonia 2 (2.3) 7 (7.9) 7 (8.0) Pyrexia 1 (1.1) 6 (6.7) 10 (11.4) Dyslipidemia 6 (6.8) 6 (6.7) 7 (8.0) Edema 1 (1.1) 2 (2.2) 5 (5.7) Leukopenia 6 (6.8) 1 (1.1) 3 (3.4) 28 CONCLUSIONS
Voclosporin 23.7mg BID dose demonstrated a statistically significantly higher CR at both weeks 24 & 48 vs. patients in the control group (p=.045); (p<.001). Voclosporin is the first therapeutic agent to meet ALL KEY 24 & 48 week pre-specified secondary endpoints in global clinical trial for active LN.
Key secondary endpoints include: time to remission/response and statistically significant reduction in UPCR and SLEDAI at 24 and 48 weeks.
This multi-target approach allowed for clinical response to be achieved using a steroid-reduced protocol. 71-76% of patients achieve a dose of ≤ 2.5 mg of oral steroids daily on or before Week 16.
Adverse events were more common in the voclosporin treated groups, but SAEs were similar to other LN trials.
Additionally, voclosporin 23.7 mg BID is associated with efficacy without hyperkalemia, hypomagnesemia or renal function deterioration over 48 weeks of treatment. This may suggest a different mechanism of action within the kidney. Further studies are needed to delineate this potential difference.
29 Principal Investigators
Principal Investigators
Ihar Adzerikhko Arturo Reyes Loaeza Olga Bugrova Samir Parikh Tak Mao Daniel Chan Elena Mikhailova Sergio Ramon Urena Tatiana Chenykh Nancy Olsen Mo Yin Mok Natalya Mitkovskaya Juanita Romero Diaz Tatiana Kameneva Ellen Ginzler Sergey Pimanov Pablo Estaley Sanson Lidia Lysenko James Tumlin Harold Michael P. Gomez Nikolay Soroka Rodolfo Araiza Casillas Tatiana Raskina Amit Saxena Joseph Antigua Magdalena Rovalo Olga Reshetko Ramesh Saxena Bernadette Heizel Reyes Boris Iliev Bogov Natalia Vezikova Richard Lafayette Llewellyn T. Hao Boriana Deliyska Stanislaw Niemczyk Tatiana Kropotina William Pendergraft III Linda Charmaine Roberto Valentin Ikonomov Antoni Sokalski Adelya Maksudova Amber Podoll Eric Amante Eduard Tilkiyan Andrezj Wiecek Vyacheslav Marasaev Michael Bubb Sandra Navarra Marian Klinger Vladimir Dobronravov Jennifer Grossman Allan Lanzon Ruth Almeida Ivan Gordeev Alejandro I Oporta Fernando Jimenez Dragan Jovanovic Mikhail Batyushin Alireza Nami Jung-Yoon Choe Faud Teran Branka Mitic Vladimir Ryasnyansky Tae Young Kang Irma Tchokhonelidze Milan Radovic Ashot Essaian Shamila De Silva Yon Su Kim Nino Tsiskarishvili Goran Radunovic Alexey Frolov Chula Herath Seung-Geun Lee Anura Hewageegana Ji Soo Lee Maynor Herrera Mendez Patricia Carreira Iryna Dudar Abdul Latiff Mohamed Nilmo Noel Chavez Perez Federico Gonzalez Olga Godlevska Nazar Jason Choo Chon Jun Xavier Fulladosa Svitlana Korneyeva A.W.M Wazil Archana Vasudevan Shue-Fen Luo Eduardo Ucar Viktoriia Vasylets Tien-Tsai Cheng Nataliya Sydor Mujibur Rahman Brancha Satirapoj Mykola Kolesnyk Syed Atiqul Haq Kajohnsak Noppakun
30